Perampanel (Fycompa; E 2007) is a highly selective, non-competitive AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptor antagonist used for adjunctive treatment of partial-onset seizures, with or without secondarily generalized seizures, in patients with epilepsy aged 12 years and older. Perampanel is chemically designated 5′-(2-cyanophenyl)-1′-phenyl-2,3′-bipyridinyl-6′(1′H)-one or 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, and is represented by the following chemical structure:

EP1300396, WO 03/047577, US 2010/0324297, WO 2007/072868 and U.S. Pat. No. 7,524,967 disclose processes for preparing of Perampanel by sequential combination of fragments (A), (B) and (C) with a 1,2-dihydro-pyridin-2-one core, using palladium-catalyzed reactions (generally represented in Scheme 1):

EP1300396 describes a process for preparing Perampanel by sequential combination of the 1,2-dihydro-pyridin-2-one core with fragments (B), (A) and (C). Example 7 discloses a process for producing Perampanel by reacting 3-(2-cyanophenyl)-5-(2-pyridyl)-2(1H)-pyridone with phenyl boronic acid, copper acetate and triethylamine in methylene chloride, followed by addition of concentrated aqueous ammonia, water and ethyl acetate.
WO 03/047577 discloses a process for preparing Perampanel by sequential coupling of the 1,2-dihydro-pyridin-2-one core with fragments (C), (A) and (B).
WO 2007/072868 and U.S. Pat. No. 7,524,967 describe a process for preparing Perampanel by combination of the 1,2-dihydropyridin-2-one core with fragments (C), (B) and (A). In this process, commercially available 2-methoxypyridine is brominated to 5-bromo-2-methoxypyridine, which is transformed to 6-methoxy-3,2′-bipyridine by reaction with n-butyllithium and 2-benzenesulfonylpyridine. Acid hydrolysis of the resulting 6-methoxy-3,2′-bipyridine gives a key intermediate—5-(2′-pyridyl)-2-pyridone (U.S. Pat. No. 7,524,967). Coupling of this compound with triphenylboroxine in the presence of copper acetate, pyridine and N,N-dimethylformamide yields 5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one, which is brominated with NBS and coupled with 2-(1,3,2-dioxaborinan-2-yl)benzonitrile in the presence of palladium acetate, triphenylphosphine and potassium carbonate in 1,2-dimethoxyethane (Scheme 2) (WO 2007/072868).

The described prior art methods use expensive reagents (palladium based catalysts and aryl boronic acids). Furthermore, palladium catalysts are used in homogeneous catalysis, which requires the step of palladium capture by post-treatment of the drug intermediate with a special absorbent, for example, by modified silica. Additional purification methods under special analytical control are used for removing traces of heavy metals (copper and palladium) from the intermediates and the final product, which increases the production cost and decreases its effectiveness.
Therefore, there continues to be a need in the art for a practical method, which does not employ heavy metals, for making Perampanel, a method that not only avoids the problems of the existing art, but is also safe, cost effective, and industrially feasible.